P520: POINT OF CARE CD19 CHIMERIC ANTIGEN RECEPTOR (CAR) T-CELLS FOR RELAPSED/REFRACTORY ACUTE MYELOID LEUKEMIA (AML) WITH ABERRANT CD19 ANTIGEN EXPRESSION
Authors: Ivetta Danylesko, Noga Shem-Tov, Ronit Yerushalmi, Elad Jacoby, Amos Toren, Orit Itzhaki, Roni Shouval, Avichai Shimoni, Avigdor Abraham, Arnon Nagler
Journal: HemaSphere (2023)

Background: Relapsed (R) and primary refractory (PR) acute myeloid leukemia (AML) and moreover relapse post allogeneic hematopoietic stem cell transplantation (allo-SCT) is associated with poor prognosis. CD19- chimeric antigen receptor (CAR)-T-cell therapies revolutionized outcomes for acute lymphoblastic leukemia (ALL). For AML identification of a target antigen is more challenging. CD19 has been shown to be aberrantly expressed in AML with t (8; 21) (q22; q22.1). Thus, we reasoned that CAR-CD19 may be beneficial for patients (pts) with R/PR t (8; 21) AML. Aims: The targeting an aberrantly expressed antigen may result in leukemia clearance without associated myelotoxicity. CD19 CAR T-cells are able to induce remission in a patient with CD19+ AML. Methods: Pts included in the analysis were treated by point of care CD19-CAR (FMC63 derived ScFv, a CD28 costimulatory domain, and CD3-zeta signaling domain) as part of a phase 2 trial (NCT02772198). Lymphodepletion included fludarabine and cyclophosphamide. CAR T-cells dose was 1 × 106/ kilogram. The response was evaluated by bone marrow (BM) aspiration on day 28. Immune effector cell-associated neurotoxicity syndrome (ICANS) and Cytokine release syndrome (CRS) were graded according to the American Society for Blood and Cellular Therapy (ASTCT). Results: Six pts (adults-5, child-1) with t (8; 21) AML (confirmed by cytogenetic and FISH) and aberrant CD19 expression were included. One patient had a complex karyotype. Molecular analysis for CKIT, NPM1, IDH1, IDH2, and CBPa were negative in all pts. One pt harbors the FLT3 ITD and one TKD mutations. Median number of previous chemotherapy (CT) lines was 4 (3-8). Four pts were with chemo resistant relapse post allo-SCT (MSD-1, 10/10 MUD -3) 5-18 months before CAR T-cells infusion. All pts developed CRS (grade 1-3) and were treated with supported treatment and 3/6 pts received i.v tocilizumab and/or dexamethasone. 2/6 pts suffered from ICANS and were treated with steroids. In 4/6 pts, day 28 BM aspiration disclosed normal hematopoiesis with no excess blasts, full donor chimerism, and lack of t(8;21) by FISH confirming clinical and cytogenetic remission (CR), while 2/6 pts with PR AML had no response. Out of the 4 responding pts, 1 remain in CR 14 months but subsequently died from CNS hemorrhage. The 2nd pt lost molecular response on day 120 (RT-PCR RUNX1-RUNX1T1/ABL - 1.024%) and underwent 2nd MUD allo- SCT but succumbed from severe sepsis. The third responding pt underwent 2nd allo-SCT from MUD 2 months after CART-cells, while in CR. Six months post-transplant the pt relapsed again, responded to azacitidine/venetoclax combination, and, was in CR for 11 months but then relapsed and died. The 4th responding pt, a 10-year-old boy, with early resistant extramedullary relapse responded to the CAR T-cells infusion and was in molecular CR including by PET-CT for 3 months but then relapsed and died (Figure 1). As for the 2 pts that did not respond, 1 received additional salvage CTX and currently underwent allo-SCT in CR; the 2nd, is a 71-year woman with refractory AML post- allo-SCT, died 1 -month post CAR T cell infusion from disease progression. Summary/Conclusion: We presented 6 pts with R/PR t (8; 21) AML with aberrant CD19 expression after multiple lines of therapies (4 post allo-SCT), treated by point of care CD19 CAR T-cells with 4 pts achieving CR. CD-19 CAR T cells administration for AML is feasible and safe. However, the response is short and should be followed by a second transplant or alternative anti leukemic therapies.Keywords: Acute myeloid leukemia, CAR-T, CD19